Spinal Cord Devices and Methods for Promoting Axonal Regeneration

ABSTRACT

A spinal cord device comprises a body formed of a biocompatible, biodegradable matrix and includes a proximal cranial surface and a distal caudal surface for connection to two ends of an injured spinal cord after removal of an injured section. The body has two sets of through channels A, B, C, D, E and F with openings in the cranial surface and the caudal surface for connection of descending motor pathways from cranial white to caudal gray matter and ascending sensory pathways from caudal white to cranial gray matter of the two spinal cord ends. The device has a transversal diameter (D t ) within a range of from  9  to  13  mm, an anteroposterior diameter (D a ) and a length (L), and the ratio anteroposterior diameter/transverse diameter (RAPT) is in a range of from  0.5  to  1.0 . Kits employ a plurality of such devices.

RELATED APPLICATIONS

This application is a continuation application under 35 U.S.C. 120 ofU.S. Application Serial No. 14/361,650 filed May 29, 2014, which is a371 of PCT/M2012/056924 filed December 3, 2012, which claimed priorityunder 35 U.S.C. 119 of U. S. Application No. 61/567,450 filed Dec. 6,2011.

FIELD OF THE INVENTION

The present invention relates to treatment of Spinal Cord Injury (SCI)and is directed to biodegradable devices having dimensions adopted tothe shape, level, size and dimensions of white and gray matter of theinjured spinal cord. These devices are to be surgically inserted at thesite of injury for promotion of axon regeneration and outgrowth forbridging a gap in the spinal cord. The devices are designed to providemotor as well as sensory connections from white to gray matter betweentwo spinal cord ends. The invention is also directed to kits comprisinga range of devices, methods for selecting an optimal device for aspecific patient, and surgical methods for implantation of a deviceaccording to the invention.

BACKGROUND OF THE INVENTION

A spinal cord injury occurs when trauma or disease damages the spinalcord and results in partial or complete paralysis. The level ofparalysis is determined by where the damage occurs, i.e. in the neck orin the back. Besides paralysis there are usually signs of sensory loss,incontinence, intractable pain and pressure sores. The world-wide annualincidence of SCI has been estimated to be around 22 per million withapproximately 2.5 million survivors living with SCI induced paralysis.As today, there is no therapy which restores or even significantlyimproves the spinal cord function in those severe cases.

Attempts to use peripheral nerve grafts for bridging spinal cord gaps inrats was reported by Cheng et al in 1996 (Science, 273: 510). The nervegrafts redirected descending motor pathways from cranial (proximal)non-permissive white matter to caudal (distal) permissive gray matterand ascending pathways from caudal white to cranial gray matter. FGF1was added to decrease gliosis and enhance axon regeneration. The nervegrafts were positioned in the gap between the two spinal cord ends andkept in the right position by tissue glue. Animals subjected to therepair procedure, i.e. implantation of nerve grafts together with FGF1,significantly improved in their hind limb function. The firstimprovements were observed a few weeks after surgery and continuedthrough one year of observation. Attempts to further improve the spinalcord repair procedures have been made by using magnetic resonanceimaging (MRI) to assess the lesion extent before surgery, see Fraidakiset al (Experimental Neurology 188(2004)33-42). Thin serial MRI sectionsallowed identification of gray and white matter and visualization ofcyst formation. After resecting the lesioned spinal cord, as necessary,autologous intercostal nerve grafts were implanted and the repair sitewas embedded in fibrin glue containing acidic FGF.

Preformed devices for bridging a gap in a spinal cord and methods formanufacture thereof, are also known from prior art, see e.g. US6,235,041 (Cheng and Olsson), U.S. Pat. No. 7,163,545 (Yaszemski et al)and WO 2007/111562 (Svensson and Mattsson). General designs aredisclosed, but there is no teaching of devices adopted for the level,size and shape of the spinal cord injury.

However, in spite of considerable time from early disclosures of thebasic principle of connecting the routing of tracts in white to graymatter, the translation into a clinically applicable method has beenabsent. Still, no product is available on the market. The spinal cord isan extremely important part of the central nervous system, where apatient with a complete injury faces a permanent loss of function belowthe site of injury, with devastating consequences for the patient'squality of life, as well as long-term costs to finance the assistance tothe patient. In many cases the patient is a fairly young person who hasbeen involved in a serious accident and will have to spend the rest oflife with no chance for functional improvements.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provideimproved devices, kits and methods for treatment of Spinal Cord Injury(SCI) and, more specifically, for bridging an injured spinal cord andpromoting axonal regeneration.

In a first embodiment, the invention is directed to a spinal cord devicefor bridging an injured spinal cord and promoting axonal regeneration,the spinal cord device comprising a body formed of a biocompatible,biodegradable matrix. The body includes a proximal, cranial surface anda distal, caudal surface for connection to two ends of an injured spinalcord after removal of an injured spinal cord section, and has throughchannels with openings in the cranial surface and the caudal surface forconnection of descending motor pathways from cranial white to caudalgray matter and ascending sensory pathways from caudal white to cranialgray matter of the two spinal cord ends. The spinal cord device has atransversal diameter (D_(t)), an anteroposterior diameter (D_(a)) and alength (L). wherein D_(t) is within a range of from 9 to 13 mm and theratio anteroposterior diameter/transverse diameter (RAPT) is in a rangeof from 0.5 to 1.0 and wherein the position and dimension of thechannels, the RAPT value, and the cranial surface area and/or the caudalsurface area of the device are adopted to the shape, level, dimension ofwhite and gray matter, and size of the injured spinal cord for optimalconnection between spinal cord tracts.

In another embodiment, the invention is directed to spinal cord devicekit comprising a plurality of devices for bridging an injured spinalcord and promoting axonal regeneration, each device comprising a bodyformed of a biocompatible, biodegradable matrix with a proximal, cranialsurface and a distal, caudal surface for connection to two ends of aninjured spinal cord after removal of an injured spinal cord section, thebody having through channels with openings in the cranial surface andthe caudal surface for connection of descending motor pathways fromcranial white to caudal gray matter and ascending sensory pathways fromcaudal white to cranial gray matter of the two spinal cord ends. Eachdevice of the kit has a transversal diameter (D_(t)), an anteroposteriordiameter (D_(a)) and a length (L), wherein the respective D_(t)'s of therespective devices in the kit are mainly evenly distributed within arange of from 9 to 13 mm and the respective ratio anteroposteriordiameter/transverse diameter (RAPT)s of the respective devices in thekit are in a range of from 0.5 to 1.0 and wherein the position anddimension of the channels, the specific RAPT value and the cranialand/or caudal surface areas of each device are adopted to a shape,level, dimension of white and gray matter, and size of an injured spinalcord for optimal connection between spinal cord tracts.

In a further embodiment, the invention is directed to method forrestoring or at least substantially restoring an injured spinal cord ofa patient, comprising the steps of i) determining the cross-sectionsurface area and the anteroposterior diameter (D_(a))/transversediameter (D_(t)) ratio (RAPT) of an injured section of the spinal cordafter resection of the nerve ends as necessary to reach healthy spinalcord tissue, ii) selecting a spinal cord device according to theinvention having the ratio anteroposterior/transverse diameter (RAPT)determined in i) and a slightly larger surface area than the spinal cordcross-section surface area to fit the dimensions of said injured sectionfor optimal connection between the spinal cord tracts, iii) optionallysoaking the device in a solution comprising one or more pharmaceuticallyactive substances, iv) positioning peripheral autologous nerves in thethrough channels, and v) implanting the device to bridge the gap in theinjured spinal cord or nerve.

The devices, kits and methods provide for improvements in the treatmentof spinal cord injuries. Various embodiments and these and additionaladvantages will be more fully described in the following detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description will be more fully understood in viewof the Drawings, in which:

FIG. 1 shows a schematic cross section of a spinal cord, where the“H”-shape represents gray matter and is surrounded by white matter.

FIG. 2 shows a schematic cross section of the end surfaces of a spinalcord device with open channels of at least two different two diametersfor insertion of nerve tissue.

FIG. 3 shows a schematic cross section of the end surfaces of a spinalcord device with open channels of three diameters for insertion of nervetissue superimposed on the spinal cord cross section. Channels A and Brepresent channel cross-section areas of descending motor tracts.Channels C, D, E and F represent cross-section areas of ascendingsensory tracts. The device diameter is approximately 1 mm larger thanthe spinal cord diameter it aims to fit.

FIG. 4 shows a schematic cross section of one specific embodiment of adevice according to the invention.

FIG. 5 shows perspective views of the channels through the device body(10) between the cranial end surface (11) and the caudal end surface(12) of the device.

FIG. 6 illustrates FGF1-dependent recovery of bilateral MEPs in thehindlimbs of treated animals as described in Example 2.

The Drawings are discussed in further detail in the detailed descriptionand are non-limiting of the invention as described.

DETAILED DESCRIPTION

The devices, kits and methods of the present invention further improvethe technique for repair of a permanently injured spinal cord byproviding devices which are adopted to the neuronal level and thedimensions, the more or less ellipsoidal cross section of the spinalcord at the injury site, as well as the length of the gap, after thespinal cord ends have been resected as required. Along a longitudinalsection of the spinal cord, the amount of white tissue decreasessuccessively from the cranial end to the caudal end and combined withthe varying degree of ellipsoidal shape, this requires that the channelsystem of the device is adopted accordingly. While not wishing to bebound by theory, the present inventors believe that one reason for thelack of viable products available for treating spinal cord injury is thefact that there has not been any device available which takes thesevarious parameters into consideration and provides a tool for optimizedregeneration of the complicated functional anatomy of the spinal cord.Precision and safety are key factors to be optimized.

Various embodiments of the invention will in the following be discussedand exemplified from the thoracic part of the spinal cord, i.e. theT2-T12 level.

The cross section of the human spinal cord at different levels isapproximated to an elliptical shape, where the wider diameter isreferred to as the transverse diameter, D_(t) and the narrower isreferred to as the anteroposterior diameter, D_(a) (see FIG. 1). Asshown in FIG. 1, the cross section of a spinal cord includes an“H”-shape of gray matter and is surrounded by white matter.

There is evidence that a regeneration strategy requires healthy andfunctional spinal cord tissue at both interfaces with the device forefficient regeneration. In other words, if a substrate for regenerationwas brought into contact with scar tissue in the injury zone, noregeneration would occur. The golden standard for determining the extentof a spinal cord injury at present is Magnetic Resonance Imaging (MRI).Unfortunately, MRI is unable to directly measure function of that spinalcord tissue. Functional evaluation of the spinal cord can be done withneurophysiology, but prior use of the technique has been restricted toevaluation of the cranial border of function in a SCI-patient. In anyregeneration strategy aiming at bridging a spinal cord gap, preoperativedetermination of the caudal border of SCI is essential, because it makesit possible to calculate the expected regeneration distance required toreach healthy tissue. To overcome this problem, a recently developednon-invasive protocol combining MRI and neurophysiology has beendescribed (Frostell et al, Spinal Cord, (2012) 50:315-319) to determineboth the functional and anatomical extent of the lesion in SCI-patients.

Briefly, electromyograms are acquired from muscles innervated by spinalcord segments above the lesion (injury), at the lesion and under thelesion. All muscles are examined both during voluntary activation aswell as activation of a patient's spasticity in the paretic part of thebody. This yields three distinct patterns of motor unit potentials(MUP): above the lesion normal MUPs are found during voluntaryactivation and no MUPs during activation of spasticity. At the level ofneurological loss, no MUPs are seen and evidence of chronic denervationindicated by positive sharp waves and fibrillation potentials are found.At a varying number of segments below the injury level, normal MUPsreappear, but not during voluntary activation—instead they appear duringspastic activation of the body part no longer in contact with the brain.The number of segments showing denervation correlated strongly to thediscontinuity of the spinal cord on MRI. By preoperative use of thedescribed approach, the exact extent of the SCI-gap can be determined,both functionally and anatomically.

The invention will in the following be illustrated by devices covering afull gap between the two ends of an injured spinal cord, but accordingto additional embodiments of the invention, a device can be designed toreplace only an injured section of the spinal cord. Instead of cutsperpendicular to the length of the spinal cord, the cord is cut in adifferent plane and the device is designed to replace the missing part.

The ratio between anteroposterior and transverse diameters, D_(a)/D_(t),is referred to as RAPT. The present inventors have now found thatdevices having combinations of transverse diameters D_(t) in the rangeof around 9-13 mm, where RAPT is within the range of 0.5-1.0, and morespecifically within the range of from 0.6-0.9, fulfills the need in themajority of situations with thoracic injuries, considering the spinalcord dimensions of the population. In a specific embodiment, theanteroposterior diameters D_(a) are in the range of around 6-10 mm. Thedevices can roughly be divided into three groups i) Round with an RAPTvalue approaching 1.00, i.e. 0.8-1.0, ii) Normal with an RAPT around0.70-0.80 and Flat with an RAPT value around 0.50-0.70. The length mayvary considerably, but a series of devices having respective lengths inthe range of from 15-40 mm fulfills this basic need in many situations.However, equipments for moulding spinal cord devices can easily beadjusted to a less usual, patient specific device length, if necessary.Accordingly, devices according to the present invention can be used insurgical treatment of a majority of spinal cord injuries. In particular,a kit comprising a series of preformed devices according to theinvention, which are substantially evenly distributed within thedimensional ranges defined above, provides a very important tool forsurgical treatment. A hospital or similar institution equipped withdevice kits according to the invention is well prepared for treatment ofa patient having a spinal cord injury which has been identified as acandidate for this type of surgical treatment. Even if a completetraumatic spinal cord injury, in particular at the thoracic level, is amajor criterion for use of a device designed for replacing a gap betweentwo fully resected ends of the spinal cord, alternative devices can beproduced for replacement of only a section of the surface area asappropriate.

Several biocompatible and/or biodegradable materials have been suggestedin prior art literature for use as implants in various parts of thebody, including the use for manufacture of spinal cord devices, and aresuitable for use in the present devices. Examples of such materials arefibrin glue, poly-L-lactic acid (PLA) polymers,poly(lactide-co-glycolide acid (PLGA) polymers, poly-glycolic acid (PGA)polymers, polycaprolactones and calcium sulphate, just to mention a few.Important functions of the material are to provide a sufficient stablematrix for manipulation of the nerve channels and to provide the desiredslow-release of medicaments of various types, to be administered at thesite for surgery, in particular growth factors. Therefore, even ifbiodegradation is a more or less continuous process, the matrix mustremain over a time sufficient for the nerve ends to grow together forsufficiently firm attachment to resist mechanical forces due tomovements by the patient. For slow-release, the matrix is preferablyporous so that it provides sufficient surface for adsorption/absorptionof the substances to be administered.

The primary choice, at present, of material for production of spinalcord devices according to the present invention, is α-calcium sulphatehemihydrate, which has a long history of clinical use and has beendemonstrated to be well tolerated with rapid and complete resorption ofthe degradation products, without any significant inflammatory response.Further, it has been used as vehicle for FGF, antibiotics and smallmolecule drugs, i.e. substances of the type that can be used also inconnection with spinal cord device implantation. The invention will, inthe following, be exemplified by one embodiment where α-calcium sulfatehemihydrate is used for manufacture of the device, but other materialsknown by a person skilled in the art can of course be used instead.

A device according to one aspect of the invention is characterized by a“cylindrical” body with more or less ellipsoidal cross section and endsurfaces as indicated by the various RAPT values discussed above. Thedevice is made of a biocompatible and biodegradable material, havingnerve guiding channels which are open, as delivered, or can optionallybe opened in connection with final preparation for surgery. A kit ofdevices according to the invention comprises a set of devices withdimensions distributed substantially evenly within the ranges definedabove. With such a kit, a hospital is well equipped for handling amajority of candidates for this kind of treatment. According to afurther embodiment of the invention, kits covering a more narrow rangeof dimensions can be provided. In one embodiment, such a narrow kit ischosen after initial pre-surgical determinations of the dimensions,while the final choice is made immediately prior to implantation, i.e.,during surgery, when the final gap in the spinal cord has been createdand the more exact dimensions can be measured in situ. Based on theinitial pre-surgical measurements, a patient specific kit can beselected and ready for the final implantation procedure, comprisingdevice selection, soaking in the appropriate solutions, and introductionof nerve tissue into the channels immediately before implantation.

In situations with only a partly injured and removed section of thespinal cord, the device is designed to cover a gap which is only asection (fraction) of the “cylindrical” end surface, where thesesections (fractions) even may be different at the two end surfaces.

According to one embodiment for fabrication of devices according to theinvention, “cylindrical” steel moulds are used. The moulds preferablyhave two ellipsoidal end plates separated by a distance h whichcorresponds to the length of the device to be produced. For creation ofnerve guiding channels in the device, several through structuresspanning the interior between the two ellipsoidal end plates are usedduring moulding. When the through structures are removed, the channelsare created. The end of each channel is positioned at a specificlocation at each end surface for optimal contact between white and graymatter. The channels can have the same cross-section over the fulllength, i.e. between the two end surfaces but can also have a funnelshape in order to connect the gray and white nerve tissue as effectivelyas possible at the two ends. In one embodiment of the invention, thecross-section area to be connected to the white matter is larger thanthe cross-section area to be connected to the gray matter.

Examples of such through structures are threads, for example suturethreads, or tubings which are fixed between specific positions at themould end surfaces defined by the topography of the white and graysubstances in the spinal cord.

In a specific embodiment for manufacturing a device, cylindrical steelmoulds are mounted in a mould fixature with end plates of a desiredellipsoidal dimension to fit the neuroanatomical shape of a resectedspinal cord. Polymer, for example, polytetrafluoroethylene (PTFE),tubings or threads are inserted between the upper end plate and thelower end plate, thereby spanning the interior of the mould and formingthe channels for later positioning of the nerve grafts. a-Calciumsulphate hemihydrate powder (or other biocompatible, biodegradablematerial) is mixed with water for injection in suitable proportions,e.g. 1:0.30 (w/v), and injected into the mould. During setting, themould is vibrated to remove air bubbles from the calcium sulphate paste.After around 1 h setting at room temperature, the device is releasedfrom the mould. Moulding generates a spinal cord device composed ofcalcium sulphate dihydrate (CaSO₄×2H₂O) as determined by x-raydiffraction analysis. The threads or tubings are at some stage removedand channels for positioning of peripheral nerve grafts are formed. Thismay be done at the manufacturing step or just prior to implantation. Byusing tubings with different dimensions, the channels for positioning ofthe peripheral nerves can be adopted for optimal connection betweenspinal cord tracts of various dimensions and at different vertebraelevels, after implantation and nerve growth. The preformed device can beprovided to the surgical team with open channels or with channels whichare opened by removing the through structures (threads or tubing), e.g.by pulling the structure out of the device, as one step in the finalpreparation for surgery. In a specific embodiment, the devices aredelivered with open channels and each of the open channels comprises athin thread which later on can be used for pulling peripheral nervesinto the channel. The device is easily equipped with such threads whenthe through structure is removed. Other ways for inserting peripheralnerves into the channels are also available, e.g. by suction.

It is known that growth factors, e.g. FGF1, play an important role innerve regeneration and nerve healing and one or more growth factors, aswell as other pharmaceutically active components are optionallyadministered to the site of implantation of a spinal cord deviceaccording to the invention. Such administration can be made in manydifferent ways, e.g. by providing the components adsorbed or absorbed tothe device. In particular, with porous or at least partly porousdevices, a sufficient surface area is available for binding thecomponent(s). According to one embodiment of the invention, the deviceprior to implantation is contacted with an aqueous solution comprisingthe component or a cocktail of components, e.g. by soaking the device inthe solution for a given time period, e.g. 10-50 ml.

Such a standard solution may comprise one or more components selectedfrom the following groups of substances: FGF1, Brain derivedneurotrophic factor (BDNF), Glial derived neurotrophic factor (GDNF),neurotrophic factor (NGF), ciliary neutrophic factor (CNTF),Chondroitinase ABC, Calcium flow antagonists increasing theregeneration, e.g. nimodipine, peptidases, S-mRNA, autologous activatedmacrophages, macrophages from donors, olfactory ensheating cells,autologous stem cells, oligodendrocyte progenitors, Schwann cells,Cortisone, angiogenesis inhibitors, erytropoetin, inactivators of Rho(e.g. Cethrin), broad spectrum antibiotics (e.g. Minocycline), Riluzoleand fysiological antagonists to the NMDA-receptor, e.g magnesium.Several additional components may be of importance , e.g.pre-degenerated peripheral nerve grafts, EGF, NT-3, PDGF, IGF1, Insulin,bFGF, HGF, Calpain inhibitor, Hematopoetic inhibitor, Inducedpluripotent stem cells, Neuronal stem cells, Embryonic stem cells,Mesenchymal stem cells, Anti Nogo, Rho antagonist, PEG and/or EPO.

For loading the device with an effective amount of FGF1, for example,the device is soaked in a solution comprising about 0.005-50microgram/ml of FGF1 for about 0.5-5 hours. In one example, theconcentration of the solution is 0.5 microgram/ml and the device issoaked for 1 hour in 30 ml solution. In additional embodiments, for evenbetter effect of FGF1, the FGF1 is mixed with heparin which binds andactivates FGF1, e.g. at a molar ratio of around 1:100. A suitable doseof the heparin-activated FGF1 to be delivered by the device is in therange of 0.01-100 ng/mg device, more specifically, 0.1-10 ng/mg device,or more specifically, 0.5-5 ng/mg device, and in particular around 1ng/mg device. After implantation, the device will deliver the activecomponent(s) over a few weeks, with the main amount being delivered overa few days.

Prior to implantation, peripheral nerves are positioned in the openchannels of the device. This can be done by pulling a nerve into each ofthe channels. The nerve can be an autologous peripheral nerve (takenfrom the patient), but can also be artificial nerve tissue produced bynerve cell culturing, preferably of nerve cells taken from the patient.After loading the device with a standard solution of pharmaceuticallyactive components or a cocktail designed for a specific patient, nervetissue is applied in each of the channels and the device is ready forimplantation.

For creating descending motor pathways from cranial (proximal) whitematter to caudal (distal) gray matter over the gap between the two endsof the spinal cord and ascending sensory pathways from caudal (distal)white matter to cranial (proximal) gray matter, the device is equippedwith several through channels. In order to obtain an appropriatecombination of pathways in the two directions, at least some of thechannels are allowed to be non-linear. In one embodiment, the device hasa first set of channels having a first diameter and a second set ofchannels having a second diameter, where the first diameter is largerthan the second diameter, as illustrated by channels A, B, C, D, E and Fin FIG. 2. In one embodiment, the channels A have a first diameter inthe range of from 2.0-2.9 mm, and one or more of channels B, C, D, E andF have a second diameter in the range of from 1.1-1.6 mm. In oneembodiment, each channel of the first diameter has a cross section areaof from about 3-7 mm² and each channel of the second diameter has across section area of 0.8-2.0 mm².

In further embodiments, the spinal cord device according to theinvention comprises channels A, B, C, D, E and F positioned as shown inFIG. 2, or comprises channels A, B, C, D, E and F positioned as shown inFIGS. 3 and 5. In a further embodiment, the spinal cord device accordingto the invention comprises channels A, B, C, D, E and F positioned andrelatively sized as shown in FIGS. 3 and 5. In a specific embodiment asshown in FIG. 3, the device comprises a third set of channels (B, C, Dand F) having a shorter diameter than the first set of channels (A) andthe second set of channels (E). In a more specific embodiment, thechannels A have a first diameter in the range of from 2.0-2.9 mm, thechannels E have a second diameter in the range of from 1.1-1.6 mm, andthe channels B, C, D and F have a third diameter of 0.5-0.9 mm. Infurther embodiments, channels A of the first diameter have a crosssection area of from about 3-7 mm², channels E of the second diameterhave a cross section area of 0.8-2.0 mm², and channels B, C, D and F ofthe third diameter have a cross section area of 0.2-0.7 mm². A morespecific embodiment is shown in FIG. 4. One or more additional sets ofchannels may be introduced in further embodiments. In all figures, onlythe channels on the left side of the symmetry plane are marked but thedesignations given are relevant also for the corresponding channels onthe right side.

The position and diameter of the through channels in each of the endsurfaces of the device is of importance in order to obtain the bestconditions for guidance of the important longitudinal tracts over thespinal cord gap. The inventors have found that, in accordance with oneembodiment of the invention, these conditions can be obtained by about12 channels, and in further embodiments the channels are positioned asillustrated in FIG. 2 or as illustrated in FIG. 3.

It is desirable to use as much surface area as possible in the spinalcord tract channels, but at the same time, the wall of each channelneeds to be thick enough so as not to be crushed during manufacture andmanipulations prior to implantation. The requirement in this respect mayvary depending on the material used and the manufacturing method. Theinventors have found that a preferred wall thickness, in particular withthe α-calcium sulphate hemihydrate used in the embodiment illustratingthe invention, is around 0.3 mm or somewhat higher. Channels A have adiameter in the range of 2.0-2.9 mm, channels B, C, D and F have adiameter in the range of 0.6-0.9 mm and channels E have a diameter inthe range of 1.1-1.6 mm. The position in each surface of the channels isillustrated in FIGS. 2 and 3 according to specific embodiments of theinvention.

Preferably, channels creating the descending motor pathway from whitematter on the cranial (proximal) side to gray matter on the caudal(distal) side, have a substantially 100% connection to the white matteron the proximal side, “the motor channel entrance”. On the caudal(distal) motor exit side, the percentage of the channel surface thatconnects to gray matter is more than 50%, e.g. in the interval 50-60%,or preferably 50-70%. According to one embodiment where the funnel typeof channels discussed above are used, an even higher percentage can beachieved, e.g. higher than 60%, 70%, 80% or 90%.

Channels creating the ascending sensory pathway from white matter on thecaudal (distal) side to gray matter on the cranial (proximal) sidepreferably have substantially 100% connection to the white matter on thedistal side. At least 60%, e.g. in the interval 60-80% of the channelopenings connects gray matter on the proximal side. This percentage canbe increased in embodiments with suitable modification of the channeldimensions, in particular funnel shaped channels.

By using the functional tracts of the white matter, it has been foundthat with the present design of the channel system it is possible toobtain good function even if the total area of white matter on thecranial (proximal) side connected to motor descending channels is low.This percentage of covered white matter is greater than 10%, and inparticular greater than 15%, e.g. covering an interval of 15-30% in oneembodiment of the invention.

The corresponding percentage of channel areas connected to ascendingsensory white matter on the caudal (distal) side is at least 5%,preferably greater than 10%, e.g. in the interval 10-20% in oneembodiment of the invention.

According to one embodiment of the invention, kits are providedcomprising a number of devices covering a desired number of alternativedimensions. One example of such a kit comprises around 10 devices withdifferent end surface dimensions and configurations, i.e., designs, andwill cover the major number of cross-section alternatives in thethoracic example. In an additional embodiment, for each of these endsurface configurations or designs, devices with different lengths areproduced. In one embodiment, at least two devices are provided havingthe same D_(t), D_(a), RAPT and Channel Diameter dimensions anddiffering lengths L. In another embodiment, for each configuration ordesign, at least two devices are provided having differing lengths L. Inanother embodiment, devices of 6 different lengths are provided for eachsurface configuration or design, whereby an example of such a kit havingten different end surface designs contains 60 devices. Again, it shouldbe stressed that this is only one example of a device kit according tothe invention.

An example of cross-sectional areas and channel diameters of a kitcomprising devices according to the invention, fulfilling a hospital'sbasic need for devices for selection in preparation for implantation ina thoracic injury situation is given below. Each of these device designsis provided with various lengths, e.g. in the 15-40 mm range. With 6lengths for each, evenly distributed within the range, a typical kitcomprises in total around 60 devices (dimensions given in mm):

Channel Diameter Design No. D_(t) D_(a) RAPT A E B, C, D, F 1 9.25 7.830.85 2.00 1.10 0.60 2 10.40 8.78 0.84 2.30 1.20 0.70 3 11.56 9.74 0.842.60 1.40 0.80 4 9.00 6.92 0.77 2.00 1.10 0.60 5 10.20 7.80 0.76 2.301.20 0.70 6 11.40 8.69 0.76 2.60 1.40 0.80 7 12.60 9.57 0.76 2.90 1.600.90 8 9.83 6.61 0.67 2.00 1.10 0.60 9 11.18 7.53 0.67 2.30 1.20 0.70 1012.58 8.45 0.67 2.60 1.40 0.80

In this example, the kit comprises 10 devices with different surfacearea dimensions and configurations, i.e., designs. However, the numberof devices in a kit can of course be different depending on the ambitionto cover gaps with different configurations.

After diagnosis, based on Mill results, which gives a rough estimate ofthe anterioposterior and transversal dimensions of the spinal cordinjury to be a candidate for spinal cord implantation, the spinal cordends are resected as necessary. The surface dimensions, i.e. D_(t) andD_(a), and the length L of the gap between the two spinal cord ends, aredetermined. This can be done in many different ways and a series ofdummies with a wide range of dimensions (D_(t), D_(a) and L) arepreferably used in situ for this determination. A device with the sameshape, but approximately 1 mm larger diameter, is selected.

The device is contacted with the solution comprising one or morepharmaceutically active component(s) to be administered to the site ofsurgery, e.g. heparin-activated FGF1. In the next step nerve tissue isintroduced into all channels in the device, and the device is thenimplanted.

EXAMPLES Example 1

This example evaluates a biodegradable calcium sulphate device withheparin-activated rhFGF1 for treatment of spinal cord injury in rat.

SCI devices fabricated from α-calcium sulfate hemihydrate with 12channels with similar geometry as shown in FIG. 5 were loaded withheparin-activated rhFGF1. The test animals, Sprague Dawley rats, wereallocated into 5 study groups. Laminectomy was carried out on allanimals independent of study group. The spinal cord of the controlgroups were either transected (group 1, negative control) or left intact(group 2, positive control). The spinal cords of the rats of groups 3-5were transected and the removed spinal cord tissue was replaced bydevices containing nerve grafts. The SCI-devices employed for studygroup 4 were soaked in 500 μg/ml heparin-activated rhFGF1(rhFGF1:heparin, 1:1, w/w). For study group 5 the SCI-devices weresoaked in 50 μg/ml heparin-activated rhFGF1. Due to autophagy, a fewanimals had to be sacrificed prior to the end of the 20 week study. Theanimals sacrificed before week 20 were evenly spread among the groups.

Before sacrifice, motor evoked potentials (MEPs) were measured in thehind limbs of the rats. The motor function of the rats was evaluatedweekly during the in-life period of the study. All animals treated withthe SCI-device, soaked in 500 or 50 μg/ml heparin-activated rhFGF1(groups 4 and 5) showed positive MEP scores in both hindlimbs at 20weeks (range 17-23) weeks) post surgery. Animals with spinal cordresection only did not demonstrate any bilateral positive MEP signals.To verify that the signal was mediated by regenerated axons, the spinalcord was re-lesioned and a second measurement was performed. None of there-lesioned animals exhibited positive MEPs.

Example 2

This example evaluates dose-finding of heparin-activated rhFGF1administered in a biodegradable calcium sulphate device for treatment ofspinal cord injury in rat.

The same type of devices as in Example 1 were used. Each device wassoaked in heparin-activated rhFGF1 (FGF1:heparin, 1:100 molar ratio)solution for 1 hat room temperature. Heparin solution withoutpreservatives (10 000 IE/ml H₂O, Leo Pharma Denmark) was employed. Thedevices were soaked in 50 μg/ml, 0.5 μg/ml, 0.005 μg/ml and 0 μg/mlconcentrations of heparin-activated rhFGF1 corresponding to a dose of45, 0.9, 0.01 and 0 ng/mg device (based on solution uptake andadsorption).

FGF1-dependent recovery of bilateral MEPs in the hindlimbs of treatedanimals is illustrated in FIG. 6. All animals showed undetectable MEPsin the hindlimbs 1 week post-surgery, while already after 2 weekspositive MEPs were recorded. The results indicate that an effective doseof heparin-activated rhFGF1 in the disclosed device in the treatment ofcomplete SCI in rat is achieved with a concentration of at least 0.5μg/ml heparin-activated rhFGF1 solution (yielding 0.9 ngheparin-activated rhFGF1/mg device) .

Example 3

Implantation of heparin-activated rhFGF1 loaded SCI-devices withperipheral nerve grafts in pig-development of operation technique andlimited safety study

Clinical SCI-devices as illustrated in FIG. 5, 15 mm high and having anoval cross section of 9.0-6.9 mm, comprising 12 channels for nerve graftpositioning are made from α-calcium sulphate hemihydrate with subsequentsterilization.

Each device is placed in 30 ml of a soaking solution consisting of 5μg/ml rhFGF1, 80 μg/ml Gentamicin, 10 mM NaPO₄, 150 mM NaCl, 0.3 mM EDTAat pH 7 for 1 hour to allow the solution to be adsorbed into the device.The heparin concentration is 430 μg/ml and the ratio rhFGF1:heparin1:100 (molar).

The animals are female Landrace pig. After 10 days of acclimatization,the pig is anaesthetized with a combination of fentanyl, midazolam andpropofol and prepared for surgery. During the surgical procedure, theintravenous anaesthesia is maintained with fentanyl 0.004 mg/kg/h,midazolam 0.5 mg/kg/h and propofol 3 mg/kg/h. The preparation forsurgery comprises disinfection of the areas subjected to surgery,combined with antibiotic treatment.

An incision is made above the large vessels in the neck and the vascularsheat is explored. A central venous catheter is inserted and secured inthe jugular vein for infusion of fluids and administration of intensivecare medications if necessary.

The pig is placed with the back up. An incision is made above thethoracic spinal cord and a laminectomy is performed. The dura mater isincised and the spinal cord is exposed. A segment large enough to fitthe SCI device of the lower thoracic spinal cord is resected.

An incision is made in the lower hind limb where after nerves, suitablefor the SCI device are exposed and resected. The nerves are trimmed intoadequate dimensions for insertion in the SCI device, which has beensoaked in the rhFGF1 solution for one hour. Subsequently, the peripheralnerves are pulled through the 12 channels in the device. The nerveendings are trimmed at the device surface and the device is insertedinto the spinal cord gap in such a way that the indicator on the deviceis dorsal and cranial. Subsequently, the SCI-device is attached to thespinal cord stumps. The dura mater is closed as well as muscle layersand skin.

Within the five days available for observation the device is partlyadhered to spinal cord.

The specific embodiments and examples set forth in the presentspecification are illustrative in nature and are not limiting of thescope of the invention defined by the present claims. Although variousaspects of the disclosed devices, kits and methods may occur to thoseskilled in the art upon reading the specification, the present inventionincludes such modifications and is limited only by the scope of theclaims.

What is claimed is:
 1. A spinal cord device for bridging an injuredhuman spinal cord and promoting axonal regeneration, the spinal corddevice comprising a body formed of a biocompatible, biodegradablematrix, the body including a proximal, cranial surface adapted forimplantation on a cranial end of an injured spinal cord and a distal,caudal surface adapted for implantation on a caudal end of an injuredspinal cord, for connection to a cranial end and a caudal end,respectively, of an injured spinal cord after removal of an injuredspinal cord section; the body having two sets of through channels A, B,C, D, E and F with openings in the cranial surface and the caudalsurface for connection of descending motor pathways from cranial whiteto caudal gray matter and ascending sensory pathways from caudal whiteto cranial gray matter of the two spinal cord ends; the spinal corddevice having a transversal diameter (D_(i)), an anteroposteriordiameter (D_(a)) and a length (L); wherein D_(t) is within a range offrom 9 to 13 mm and the ratio anteroposterior diameter/transversediameter (RAPT) is in a range of from 0.5 to 1.0; wherein (a) the twosets of channels A-F are symmetrically arranged in each of the cranialsurface and the caudal surface of the device at locations correspondingwith anatomical positions in the cranial end and caudal end,respectively, of the removed spinal cord section, (b)(i) in the cranialsurface: the channels A are positioned in opposite lateral funiculi andadjacent opposite posterior horns, the channels B are positioned inopposite anterior funiculi and adjacent the ends of opposite anteriorhorns, the channels C are positioned in gray matter at the ends ofopposite posterior horns, the channels D are positioned in the posteriorhorns, between channels C and the lateral horns, the channels E arepositioned in the posterior horns, between the channels D and thelateral horns, and the channels F are positioned in the anterior horns,between the channels B and the lateral horns, and (b)(ii) in the caudalsurface: the channels A are positioned at the juncture of the respectiveanterior horn, posterior horn and the intermediate gray, the channels Bare positioned in gray matter at the ends of opposite anterior horns andin opposite anterior funiculi adjacent the ends of the respectiveanterior horns, the channels C are positioned in opposite posteriorfuniculi and between the ends of opposite posterior horns, the channelsD are positioned in opposite posterior funiculi and between the oppositechannels C, the channels E are positioned in opposite posterior funiculiand between the openings for channels D and the intermediate graymatter, and the channels F are positioned in opposite lateral funiculiand adjacent the respective anterior funiculi, and (c)(i) channels Ahave a first diameter in a range of from 2.0-2.9 mm, and one or more ofchannels B, C, D, E and F have a second diameter in a range of from1.1-1.6 mm, or (c)(ii) channels A have a first diameter in a range offrom 2.0-2.9 mm, channels E have a second diameter in a range of from1.1-1.6 mm, and channels B, C, D and F have a third diameter in a rangeof from 0.5-0.9 mm.
 2. A spinal cord device according to claim 1,wherein the device has been soaked in a solution comprising one or morepharmaceutically active substances.
 3. A spinal cord device according toclaim 1, wherein the device has been soaked in a solution comprisingFGF1.
 4. A spinal cord device according to claim 1, wherein Da is in therange of 6-10 mm.
 5. A spinal cord device according to claim 1, whereinRAPT is in the range of 0.6-0.9.
 6. A spinal cord device according toclaim 1, wherein L is in the range of 15-40 mm.
 7. A spinal cord devicekit, comprising a plurality of devices according to claim 1, wherein therespective D_(t)'s of the respective devices in the kit are distributedwithin a range of from 9 to 13 mm and the respective ratioanteroposterior diameter/transverse diameter (RAPT)s of the respectivedevices in the kit are in a range of from 0.5 to 1.0.
 8. A spinal corddevice kit according to claim 7, comprising at least 10 spinal corddevices, each having a cross-section with channels A, B, C, D, E and F,wherein the 10 spinal cord devices respectively have the following 10designs, with dimensions in mm: Channel Diameter Design No. D_(t) D_(a)RAPT A E B, C, D, F 1 9.25 7.83 0.85 2.00 1.10 0.60 2 10.40 8.78 0.842.30 1.20 0.70 3 11.56 9.74 0.84 2.60 1.40 0.80 4 9.00 6.92 0.77 2.001.10 0.60 5 10.20 7.80 0.76 2.30 1.20 0.70 6 11.40 8.69 0.76 2.60 1.400.80 7 12.60 9.57 0.76 2.90 1.60 0.90 8 9.83 6.61 0.67 2.00 1.10 0.60 911.18 7.53 0.67 2.30 1.20 0.70 10 12.58 8.45 0.67 2.60 1.40 0.80


9. A spinal cord device kit according to claim 8, wherein the kitincludes at least two devices having the same D_(t), D_(a), RAPT andChannel Diameter dimensions and differing lengths L.
 10. A spinal corddevice kit according to claim 8, comprising at least two devices foreach of Designs 1-10, the respective devices for each Design havingdiffering lengths L.
 11. A spinal cord device kit according to claim 8,comprising at least six devices for each of Designs 1-10, the respectivedevices for each Design having differing lengths L.
 12. A spinal corddevice kit according to claim 7, wherein the kit includes at least twodevices having the same D_(t), D_(a), RAPT and Channel Diameterdimensions and differing lengths L.